Organic compounds

ABSTRACT

The present invention relates to a new use of phosphodiesterase 1 (PDE1) inhibitors for the treatment and/or prophylaxis of narcolepsy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. filing under 35 U.S.C. 371 ofPCT/US2007/023854 filed on Nov. 13, 2007, which claims the benefit of60/858,732 filed on Nov. 13, 2006 and 60/873,175 filed on Dec. 5, 2006,the contents of each of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a new use for compounds that inhibitphosphodiesterase 1 (PDE1), e.g., that inhibit PDE1-mediated suppressionof the dopamine D1 receptor intracellular pathway, specifically for thetreatment of narcolepsy.

BACKGROUND OF THE INVENTION

Narcolepsy is a chronic neurological disorder caused by the brain'sinability to regulate sleep-wake cycles normally. At various timesthroughout the day, people with narcolepsy experience fleeting urges tosleep. If the urge becomes overwhelming, patients fall asleep forperiods lasting from a few seconds to several minutes. In rare cases,some people may remain asleep for an hour or longer.

Narcoleptic sleep episodes can occur at any time, often without warning,and may be quite dangerous if patients are driving or operatingmachinery. In addition to daytime sleepiness, patients may experiencecataplexy, or the sudden loss of voluntary muscle tone; vividhallucinations during sleep onset or upon awakening; brief episodes oftotal paralysis at the beginning or end of sleep; and/or automaticbehavior, such as talking or performing routine activities during asleep episode but having no memory of these activities upon waking. Mostpatients also experience frequent awakenings during nighttime sleep. Forthese reasons, narcolepsy is considered to be a disorder of the normalboundaries between the sleeping and waking states.

Eleven families of phosphodiesterases (PDEs) have been identified butonly PDEs in Family I, the Ca²⁺-calmodulin-dependent phosphodiesterases(CaM-PDEs), have been shown to mediate the calcium and cyclic nucleotide(e.g. cAMP and cGMP) signaling pathways. The three known CaM-PDE genes,PDE1A, PDE1B, and PDE1C, are all expressed in central nervous systemtissue. PDE1A is expressed throughout the brain with higher levels ofexpression in the CA1 to CA3 layers of the hippocampus and cerebellumand at a low level in the striatum. PDE1A is also expressed in the lungand heart. PDE1B is predominately expressed in the striatum, dentategyms, olfactory tract and cerebellum, and its expression correlates withbrain regions having high levels of dopaminergic innervation. AlthoughPDE1B is primarily expressed in the central nervous system, it may bedetected in the heart. PDE1C is primarily expressed in olfactoryepithelium, cerebellar granule cells, and striatum. PDE1C is alsoexpressed in the heart and vascular smooth muscle.

Cyclic nucleotide phosphodiesterases downregulate intracellular cAMP andcGMP signaling by hydrolyzing these cyclic nucleotides to theirrespective inactive 5′-monophosphates (5′AMP and 5′GMP). CaM-PDEs play acritical role in mediating signal transduction in brain cells,particularly within an area of the brain known as the basal ganglia orstriatum. For example, NMDA-type glutamate receptor activation and/ordopamine D2 receptor activation result in increased intracellularcalcium concentrations, leading to activation of effectors such ascalmodulin-dependent kinase (CaMKII) and calcineurin and to activationof CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine D1 receptoractivation, on the other hand, leads to activation of calcium dependentnucleotide cyclases, resulting in increased cAMP and cGMP. These cyclicnucleotides in turn activate protein kinase A (PKA; cAMP-dependentprotein kinase) and/or protein kinase G (PKG; cGMP-dependent proteinkinase) that phosphorylate downstream signal transduction pathwayelements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein)and cAMP responsive element binding protein (CREB).

CaM-PDEs can therefore affect dopamine-regulated and other intracellularsignaling pathways in the basal ganglia (striatum), including but notlimited to nitric oxide, noradrenergic, neurotensin, CCK, VIP,serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP) and endorphin intracellularsignaling pathways.

Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1(PDE1) activity, functions in brain tissue as a regulator of locomotoractivity and learning and memory. PDE1 is a therapeutic target forregulation of intracellular signaling pathways, preferably in thenervous system, including but not limited to a dopamine D1 receptor,dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK,VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP) or endorphin intracellularsignaling pathway. For example, inhibition of PDE1B may potentiate theeffect of a dopamine D1 agonist by protecting cGMP and cAMP fromdegradation, and similarly inhibit dopamine D2 receptor signalingpathways, by inhibiting PDE1 activity. PDE1 inhibitors are thereforepotentially useful in diseases characterized by reduced dopamine D1receptor signaling activity. See generally, WO 03/020702.

EP 0201188 and EP 0911333, the contents of which are incorporated hereinby reference, disclose certain 1,3,5,-substituted,6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one compounds, claimed to beuseful for treatment of cardiovascular disease, erectile dysfunction,and other disorders. These compounds are not, however, taught orsuggested to be useful for the treatment of diseases involving disordersof the dopamine D1 receptor intracellular pathway, particularly diseasesrelating to sleep disorders such as narcolepsy. PCT/US2006/33179, thecontents of which are incorporated herein by reference, discloses theuse of 1,3,5,-substituted, 6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-onecompounds for treatment of diseases involving disorders of the dopamineD1 receptor intracellular pathway, but does not specifically disclosethe use of such compounds in the treatment or prophylaxis of narcolepsy.PCT/US2006/022066, the contents of which are incorporated herein byreference, discloses PDE1 inhibitors which are 7,8-dihydro-[1H or2H]-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or7,8,9-trihydro-[1H or2H]-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones, but does notspecifically disclose their use for the treatment or prophylaxis ofnarcolepsy. WO 03/042216, U.S. Pat. No. 5,939,419, EP 0 538 332, U.S.Pat. No. 5,393,755, U.S. Pat. No. 6,969,719 B2, Xia et al., J. Med.Chem. (1997), 40, 4372-4377 and Ahn et al., J. Med. Chem. (1997), 40,2196-2210, the contents of all of which are incorporated herein byreference, disclose PDE1 cGMP phosphodiesterase inhibitors which aresubstituted pyrazolo[3,4-d]pyrimidine, pyrimido[2,1-b]purin-4-one andimidazo[2,1-b]purin-4-one analogues useful for the treatment ofhypertensive, cardiovascular, sexual dysfunction and other cGMP-PDEVrelated disorders, but do not specifically disclose their use for thetreatment or prophylaxis of narcolepsy.

SUMMARY OF THE INVENTION

The invention provides a new method of treatment or prophylaxis fornarcolepsy comprising administering an effective amount of aphosphodiesterase-1 (PDE1) inhibitor to a patient in need thereof. PDE1inhibitors include, for example, 7,8-dihydro-[1H or2H]-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or7,8,9-trihydro-[1H or2H]-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones, substituted atthe 1 or 2 position with C₂₋₉ alkyl or C₃₋₉ cycloalkyl, or optionallysubstituted heteroarylalkyl or substituted arylalkyl, in free, salt orprodrug form (hereinafter a PDE 1 Inhibitor, e.g., as described below)or a 1,3,5-substituted 6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one, infree, salt or prodrug form (also included in PDE 1 Inhibitors, e.g., asdescribed below), to a patient in need thereof.

PDE1 inhibitors also include, for example, substitutedimidazo[2,1-b]purin-4-one, e.g.,(6aR,9aS)-2-(biphenyl-4-ylmethyl)-5,6a,7,8,9,9a-hexahydro-5-methyl-3(phenylmethyl)-cyclopent-[4,5]imidazo-[2,1-b]purin-4(3H)-one,(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2,3-bis(phenylmethyl)cyclopent-[4,5]imidazo-[2,1-b]purin-4(3H)-one,5′-methyl-2′,3′-bis(phenylmethyl)spiro[cyclopentane-1,7′(8′H)-[3H]imidazo[2,1-b]purin]-4′(5′H)-one,or5′-methyl-2′-(biphenylylmethyl)-3′-(phenylmethyl)spiro[cyclopentane-1,7′(8′H)-[3H]imidazo[2,1-b]purin]-4′(5′H)-oneas described in Ahn et al., J. Med. Chem. (1997), 40, 2196-2210(hereinafter a PDE 1 Inhibitor, e.g., as described below). Thesecompounds are found to selectively inhibit phosphodiesterase 1 (PDE1)activity, especially PDE1B activity, and to be useful in the treatmentand prophylaxis of narcolepsy. These compounds are found to selectivelyinhibit phosphodiesterase 1 (PDE1) activity, especially PDE1B activity,and to be useful in the treatment and prophylaxis of narcolepsy.

DETAILED DESCRIPTION OF THE INVENTION Compounds for Use in the Methodsof the Invention

Preferably, the PDE 1 Inhibitors for use in the methods of treatmentdescribed herein are a 7,8-dihydro-[1H or2H]-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or7,8,9-trihydro-[1H or2H]-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones, of formula I

wherein

-   -   (i) R₁ is H or C₁₋₄ alkyl (e.g., methyl);    -   (ii) R₄ is H or C₁₋₄ alkyl and R₂ and R₃ are, independently, H        or C₁₋₄ alkyl (e.g., R₂ and R₃ are both methyl, or R₂ is H and        R₃ is isopropyl), aryl, heteroaryl, (optionally        hetero)arylalkoxy, or (optionally hetero)arylalkyl;    -   or    -   R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (iii) R₅ is a substituted heteroarylalkyl, e.g., substituted        with haloalkyl    -   or    -   R₅ is attached to one of the nitrogen atoms on the pyrazolo        portion of Formula I and is a moiety of Formula Q

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H or halogen (e.g., Cl or F), and R₁₀ is halogen,alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g.,phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), orthiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl,tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g.,methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided thatwhen X, Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is notpresent; and

-   -   (iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl),        arylamino (e.g., phenylamino), heteroarylamino,        N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino        (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino); and    -   (v) n=0 or 1;    -   (vi) when n=1, A is —C(R₁₃R₁₄)—    -   wherein R₁₃ and R₁₄, are, independently, H or C₁₋₄ alkyl, aryl,        heteroaryl, (optionally hetero)arylalkoxy or (optionally        hetero)arylalkyl;        in free, salt or prodrug form, including its enantiomers,        diasterisomers and racemates.

The invention further provides the use of PDE 1 Inhibitors of Formula Ias follows:

-   -   1.1 Formula I wherein R₁ is methyl and n=0;    -   1.2 Formula I or 1.1 wherein R₄ is H or C₁₋₄ alkyl and at least        one of R₂ and R₃ is lower alkyl, such that when the carbon        carrying R₃ is chiral, it has the R configuration, e.g., wherein        both R₂ and R₃ are methyl, or wherein one is hydrogen and the        other isopropyl;    -   1.3 Formula I or 1.1 wherein R₄ is H and at least one of R₂ and        R₃ is arylalkoxy;    -   1.4 Formula I wherein R₁ is methyl, R₂, R₃, and R₄ are H, n=1,        and R₁₃ and R₁₄ are, independently, H or C₁₋₄ alkyl (e.g.,        methyl or isopropyl);    -   1.5 Formula I or 1.1 wherein R₂ is H and R₃ and R₄ together form        a tri- or tetramethylene bridge, having the cis configuration,        preferably wherein the carbons carrying R₃ and R₄ have the R and        S configurations respectively;    -   1.6 Formula I, 1.1 or 1.5 wherein R₅ is a substituted        heteroarylmethyl, e.g., para-substituted with haloalkyl;    -   1.7 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety        of Formula Q wherein R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is        phenyl;    -   1.8 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety        of Formula Q wherein R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is        pyridyl or thiadiazolyl;    -   1.9 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety        of Formula Q wherein R₈, R₉, R₁₁, and R₁₂ are, independently, H        or halogen, and R₁₀ is haloalkyl;    -   1.10 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety        of Formula Q wherein R₈, R₉, R₁₁, and R₁₂ are, independently, H,        and R₁₀ is alkyl sulfonyl;    -   1.11 any of the preceding formulae wherein R₅ is attached to the        2-position nitrogen on the pyrazolo ring;    -   1.12 any of the preceding formulae wherein R₆ is benzyl;    -   1.13 any of the preceding formulae wherein R₆ is phenylamino or        phenylalkylamino (e.g., benzylamino);    -   1.14 any of the preceding formulae wherein R₆ is phenylamino;    -   1.15 any of the preceding formulae wherein X, Y, and Z are all        C,    -   1.16 any of the preceding formulae wherein X, Y, and Z are all C        and R₁₀ is phenyl or 2-pyridyl; and/or    -   1.17 any of the preceding formulae wherein the compounds inhibit        phosphodiesterase-mediated (e.g., PDE1-mediated, especially        PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC₅₀ of less        than 1 μM, preferably less than 25 nM in an immobilized-metal        affinity particle reagent PDE assay, for example, as described        in Example 1;        in free or salt form.

For example, the PDE 1 Inhibitors include 7,8-dihydro-[1H or2H]-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones of Formula Ia

wherein

-   -   (i) R₁ is H or C₁₋₄ alkyl [e.g., methyl];    -   (ii) R₄ is H and R₂ and R₃ are, independently, H or C₁₋₄ alkyl        [e.g., R₂ and R₃ are both methyl, or R₂ is H and R₃ is        isopropyl], aryl, or arylalkyl;    -   or R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge [pref. wherein the R₃ and R₄ have the cis        configuration, e.g., where the carbons carrying R₃ and R₄ have        the R and S configurations respectively];    -   (iii) R₅ is attached to one of the nitrogen atoms on the        pyrazolo portion of formula Ia and is a substituted benzyl of        formula Qa

-   -   wherein R₈, R₉, R₁₁ and R₁₂ are independently H or halogen        (e.g., Cl or F); and R₁₀ is halogen, alkyl, cycloalkyl,        haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),        heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or        thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), arylcarbonyl (e.g.,        benzoyl), alkyl sulfonyl or heteroarylcarbonyl; and    -   (iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl [e.g., benzyl],        arylamino [e.g., phenylamino], heteroarylamino, arylalkylamino,        N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino        [e.g. N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino];        in free, salt or prodrug form.

The invention further provides the use of PDE 1 Inhibitors of Formula Iaas follows:

-   -   2.1: Formula Ia wherein R₁ is methyl;    -   2.2: Formula Ia or 2.1 wherein R₄ is H and at least one of R₂        and R₃ is lower alkyl, such that when the carbon carrying R₃ is        chiral, it has the R configuration, e.g., wherein both R₂ and R₃        are methyl, or wherein one is hydrogen and the other isopropyl;    -   2.3: Formula Ia or 2.1 wherein R₂ is H and R₃ and R₄ together        form a tri- or tetramethylene bridge, having the cis        configuration, preferably wherein the carbons carrying R₃ and R₄        have the R and S configurations respectively;    -   2.4: Formula Ia, 2.1, 2.2 or 2.3 wherein R₅ is a moiety of        formula Qa wherein R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is phenyl;    -   2.5: Formula Ia, 2.1, 2.2, or 2.3 wherein R₅ is a moiety of        formula Qa wherein R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is pyridyl        or thiadiazolyl;    -   2.6: Formula Ia, 2.1, 2.2, 2.3, 2.4, or 2.5 wherein R₅ is        attached to the 2-position nitrogen on the pyrazolo ring;    -   2.7: Formula Ia, 2.1, 2.2, 2.3, 2.4, 2.5 or 2.6 wherein R₆ is        benzyl;    -   2.8: Formula Ia, 2.1, 2.2, 2.3, 2.4, 2.5 or 2.6 wherein R₆ is        phenylamino or phenylalkylamino (e.g., benzylamino); and/or    -   2.9: Formula Ia, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, or 2.8        wherein the compounds inhibit phosphodiesterase-mediated (e.g.,        PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP,        e.g., with an IC₅₀ of less than 1 μM, preferably less than 25 nM        in an immobilized-metal affinity particle reagent PDE assay, for        example, as described in Example 1;    -   in free or salt form.

In an another embodiment, the PDE 1 Inhibitors are compounds of FormulaI wherein

-   -   (i) R₁ is methyl;    -   (ii) R₂, R₃ and R₄ are H;    -   (iii) n=1 and R_(a) and R_(b) are, independently, H or methyl;    -   (iv) R₅ is a moiety of Formula Q wherein R₈, R₉, R₁₁ and R₁₂ are        H and R₁₀ is phenyl, pyridyl (for example pyrid-2-yl), or        thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl);    -   (v) R₆ is benzyl, phenylamino or benzylamino;    -   in free or salt form.

In another embodiment, the PDE 1 Inhibitors are compounds of Formula Iwherein

-   -   (i) R₁ is methyl;    -   (ii) n=0;    -   (iii) R₂ is H and R₃ and R₄ together form a tri- or        tetra-methylene bridge [pref. with the carbons carrying R₃ and        R₄ having the R and S configuration respectively]; or at least        one of R₂ and R₃ is methyl, isopropyl or arylalkoxy and R₄ is H;        or R₂ and R₃ are H and R₄ is a C₁₋₄ alkyl;    -   (iv) R₅ is a substituted heteroarylmethyl, e.g.,        para-substituted with haloalkyl; or    -   R₅ is a moiety of Formula Q wherein R₈, R₉, R₁₁ and R₁₂ are H or        halogen and R₁₀ is haloalkyl, phenyl, pyridyl (for example        pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); and    -   (v) R₆ is benzyl, phenylamino or benzylamino;    -   in free or salt form.

In another embodiment, the PDE 1 Inhibitors are compounds of Formula Iawherein

-   -   (i) R₁ is methyl;    -   (ii) R₂ is H and R₃ and R₄ together form a tri- or        tetra-methylene bridge [pref. with the carbons carrying R₃ and        R₄ having the R and S configuration respectively]; or R₂ and R₃        are each methyl and R₄ is H; or R₂ and R₄ are H and R₃ is        isopropyl [pref. the carbon carrying R₃ having the R        configuration];    -   (iii) R₅ is a moiety of Formula Qa wherein R₈, R₉, R₁₁, and R₁₂        are H and R₁₀ is haloalkyl, phenyl, pyridyl (for example        pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl); and    -   (iv) R₆ is benzyl, phenylamino or benzylamino;    -   in free or salt form.

In another embodiment, the PDE 1 Inhibitors are compounds of Formula Iaselected from the following:

For example, PDE 1 Inhibitors include compounds according to FormulaeII, III and IV.

wherein

-   -   R_(a) and R_(b) are, independently, H or C₁₋₄ alkyl;    -   R₆ is phenylamino or benzylamino;    -   R₁₀ is phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl        (e.g., 1,2,3-thiadiazol-4-yl);    -   in free or salt form.

wherein

-   -   R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene        bridge [pref. with the carbons carrying R₃ and R₄ having the R        and S configuration respectively]; or at least one of R₂ and R₃        is methyl, isopropyl or arylalkoxy and R₄ is H; or R₂ and R₃ are        H and R₄ is a C₁₋₄ alkyl;    -   R₆ is phenylamino or benzylamino;    -   R₁₀ is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or        thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl);    -   in free or salt form.

wherein

-   -   R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene        bridge [pref. with the carbons carrying R₃ and R₄ having the R        and S configuration respectively]; or at least one of R₂ and R₃        is methyl, isopropyl or arylalkoxy and R₄ is H; or R₂ and R₃ are        H and R₄ is a C₁₋₄ alkyl;    -   R₆ is phenylamino or benzylamino;    -   R₁₀ is phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl        (e.g., 1,2,3-thiadiazol-4-yl);    -   in free or salt form.

PDE 1 Inhibitors used in the method disclosed herein also includecompounds according to Formula V:

-   -   wherein    -   R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene        bridge [pref. with the carbons carrying R₃ and R₄ having the R        and S configuration respectively]; or    -   R₂ and R₃ are each methyl and R₄ is H; or R₂ and R₄ are H and R₃        is isopropyl [pref. the carbon carrying R₃ having the R        configuration];    -   R₆ is phenylamino or benzylamino;    -   R₁₀ is phenyl, pyridyl, or thiadiazolyl;    -   in free or salt form.        In a preferred embodiment, the PDE 1 Inhibitors for use in the        methods of treatment described herein are a 1,3,5-substituted        6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one, of formula VI

wherein

-   -   R_(a) is methyl or C₂-C₆ alkyl;    -   R₁ is H or C₁-C₄ alkyl;

each of R₂ and R₃ is independently selected from H and C₁-C₄ alkyl, orR₂ is H or C₁-C₄ alkyl and R₃ is OH, C₂-C₄ alkanoyloxy or fluoro, or R₂and R₃ when taken together represent C₂-C₆ alkylene, or R₂ and R₃ whentaken together with the carbon atom to which they are attached representa carbonyl group;

-   -   Ar is either (a)

wherein

-   -   each of R₄, R₅ and R₆ is independently selected from        -   H        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkoxy-Z—,        -   halo,        -   halo(C₁-C₄)alkyl,        -   phenoxy, optionally substituted by up to three substitutents            each of which substitutent is independently selected from            halo, C₁₋₄ alkyl, and C₁-C₄ alkoxy,        -   nitro,        -   hydroxy,        -   hydroxy-Z—,        -   C₂-C₄ alkanoyl,        -   amino,        -   amino-Z—,        -   (C₁-C₄ alkyl)NH,        -   (C₁-C₄ alkyl)₂N—,        -   (C₁-C₄ alkyl)NH—Z—,        -   (C₁-C₄ alkyl)₂N—Z—,        -   —COOH,        -   —Z—COOH,        -   —COO(C₁-C₄ alkyl),        -   —Z—COO(C₁-C₄ alkyl)        -   C₁-C₄ alkanesulphonamido,        -   C₁-C₄ alkanesulphonamido-Z—,        -   halo(C₁-C₄)alkanesulphonamido,        -   halo(C₁-C₄)alkanesulphonamido-Z—,        -   C₁-C₄ alkanamido,        -   C₁-C₄ alkanamido-Z—,        -   HOOC—Z—NH—,        -   HOOC—Z—NH—Z—,        -   (C₁-C₄ alkyl)OOC—Z—NH—,        -   (C₁-C₄ alkyl)OOC—Z—NH—Z—,        -   C₁-C₄ alkyl-NH—SO₂—NH—,        -   C₁-C₄ alkyl-NH—SO₂—NH—Z—,        -   (C₁-C₄ alkyl)₂-N—SO₂—NH—,        -   (C₁-C₄ alkyl)₂-N—SO₂—NH—Z—,        -   C₁-C₄ alkoxy CH═CH—Z—CONH—,        -   C₁-C₄ alkoxy CH═CHCONH        -   C₁-C₄ alkyl-SO₂—N(C₁-C₄ alkyl)-,        -   C₁-C₄ alkyl-SO₂—N(C₁-C₄ alkyl)-Z—,        -   (C₁-C₄ alkyl)NH—Z—SO₂—NH—,        -   (C₁-C₄ alkyl)₂N—Z—SO₂—NH—,        -   (C₁-C₄ alkyl)NH—Z—SO₂—NH—Z—,        -   (C₁-C₄ alkyl)₂N—Z—SO₂—NH—Z—,    -   benzenesulphonamido, optionally ring substituted by up to three        substitutents each of which is independently selected from halo,        C₁₋₄ alkyl, and C₁-C₄ alkoxy,        -   C₁-C₄ alkanoyl-N(C₁-C₄ alkyl)-,        -   C₁-C₄ alkanoyl-N(C₁-C₄ alkyl)-Z—,        -   C₁-C₄ alkoxycarbonyl-CH(CH₂OH)NHSO₂—,        -   —SO₃H,        -   —SO₂NH₂,        -   H₂NOC—CH(CH₂OH)—NHSO₂—,        -   HOOC—Z—O—, and        -   (C₁-C₄ alkyl)OOC—Z—O—,    -   or optionally one of R₄, R₅ and R₆ is a G-Het group and wherein        the others of R₄, R₅ and R₆ are independently selected from the        R₄, R₅ and R₆ substitutents listed above;    -   Z is C₁-C₄ alkylene,    -   G is a direct link, Z, O, —SO₂NH—, SO₂, or —Z—N(C₁-C₄        alkyl)SO₂—,    -   Het is a 5- or 6-membered heterocyclic group containing 1, 2, 3        or 4 nitrogen heteroatoms; or 1 or 2 nitrogen heteroatoms and 1        sulphur heteroatom or 1 oxygen heteroatom; or the heterocyclic        group is furanyl or thiophenyl; wherein the Het group is        saturated or partially or fully unsaturated and optionally        substituted by up to 3 substitutents, wherein each substitutent        is independently selected from C₁-C₄ alkyl, oxo, hydroxy, halo,        and halo(C₁-C₄) alkyl;    -   or (b) any one of the following bicyclic groups:        -   benzodioxolanyl,        -   benzodioxanyl,        -   benzimidazolyl,        -   quinolinyl,        -   indolyl,        -   quinazolinyl,        -   isoquinolinyl,        -   benzotriazolyl,        -   benzofuranyl,        -   benzothiophenyl,        -   quinoxalinyl, or        -   phthalazinyl,    -   wherein said bicyclic Ar groups are linked to the neighbouring        —C(R₂R₃)— group via the benzo ring portion,    -   and wherein the heterocyclic portion of said bicyclic Ar group        is optionally partially or fully saturated, said group being        optionally substituted by one or more of C₁-C₄ alkyl, halo,        hydroxy, oxo, amino, and C₁-C₄ alkoxy;

or a pharmaceutically acceptable salt of the compound, or apharmaceutically acceptable solvate of the compound or the salt.

For example, PDE 1 Inhibitors for use in the present invention include1,3,5,-substituted, 6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one, infree or pharmaceutically acceptable salt form, particularly compounds ofFormula VI or the following formulae:

-   -   3.2 Of Formula VI wherein R_(a) is a C₂₋₅ alkyl group;    -   3.3 Of Formula VI wherein R_(a) is a C₂₋₄ alkyl group;    -   3.4 Of Formula VI wherein R_(a) is a C₃ alkyl group;    -   3.5 Of Formula VI wherein R_(a) is methyl;    -   3.6 Of Formula VI, 3.2, 3.3, 3.4 or 3.5 wherein R₁ is a C₁₋₆        alkyl group;    -   3.7 Of any of the preceding formulae wherein R₁ is a C₁₋₃ alkyl        group;    -   3.8 Of any of the preceding formulae wherein R₁ is a methyl        group;    -   3.9 Of any of the preceding formulae wherein R₂ is H,    -   3.10 Of any of the preceding formulae wherein R₃ is H,    -   3.11 Of any of the preceding formulae wherein R₄, R₅ and R₆ are        independently selected from H, (C₁₋₄ alkyl)₂N—, C₁₋₄        alkanesulphonamido and benzenesulphonamido;    -   3.12 Of any of the preceding formulae wherein R₄, R₅ and R₆ are        independently selected from H, diethylamino, methanesulphonamido        and benzenesulphonamido;    -   3.13 Of any of the preceding formulae wherein Ar is        4-diethylaminophenyl;    -   3.14 Of any of the preceding formulae wherein Ar is        2-methanesulphonamidophenyl;    -   3.15 Of any of the preceding formulae wherein Ar is        4-benzenesulphonamidophenyl;    -   3.16 Of any of the preceding formulae wherein one of R₄, R₅ and        R₆ is (C₁₋₄ alkyl)₂N— and wherein the other two of R₄, R₅ and R₆        are H.    -   3.17 Of any of the preceding formulae wherein one of R₄, R₅ and        R₆ is diethylamino and wherein the other two of R₄, R₅ and R₆        are H.    -   3.18 Of any of the preceding formulae wherein R_(a) is methyl;    -   3.19 Of any of the preceding formulae wherein R_(a) is C₂-C₆        alkyl;    -   3.20 Of any of the preceding formulae wherein the compound is        selected from the following:

-   -   3.21 Of any of the preceding formulae wherein the compound is

-   -   in free or salt form;    -   3.22 A compound which is a 1,3,5,-substituted,        6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one, in free or        pharmaceutically acceptable salt form, e.g. a compound of        Formula VI or according to any of formulae 3.2-3.21, wherein the        compound inhibits phosphodiesterase-mediated (e.g.,        PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP,        e.g., with an IC₅₀ of less than 1 μM, preferably less than 25 nM        in an immobilized-metal affinity particle reagent PDE assay, for        example, as described in Example 1 below.

In another embodiment, the PDE 1 Inhibitors for use in the methods oftreatment described herein are substituted (imidazo, pryimido ordiazepino)[2,1-b]purin-4-ones of Formula VIIa or VIIb:

in free, salt or prodrug form, including its enantiomers, diasterisomersand racemates, wherein:

-   -   i) q=0, 1 or 2;    -   ii) R¹, R^(a), R^(b), R^(c) and R^(d) are each independently H,        alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups,        -   wherein each alkyl group of R¹, R^(a), R^(b), R^(c) and            R^(d) is independently unsubstituted or substituted with 1            to 5 independently selected R³ moieties which can be the            same or different, each R³ moiety being independently            selected from the group consisting of hydroxy, alkoxy,            cycloalkoxy, aryloxy, alkylthio, arylthio, aryl, haloaryl,            heteroaryl, cycloalkyl, heterocycloalkyl, amino, alkylamino,            dialkylamino, cycloalkylamino and heterocycloalkylamino            groups;        -   wherein each of the aryl, heteroaryl, cycloalkyl and            heterocycloalkyl groups of R¹, R^(a), R^(b), R^(c) and R^(d)            is independently unsubstituted or substituted with 1 to 5            independently selected R⁴ moieties which can be the same or            different, each R⁴ moiety being independently selected from            the group consisting of: halo, optionally substituted aryl            (e.g., phenyl, chlorophenyl, methoxyphenyl), heteroaryl            (e.g., pyridyl, pyrrolyl), nitro, cyano, haloalkyl,            haloalkoxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl            (e.g., pyrrolidinyl, morpholin-4-yl, pyrrol-1-yl),            cycloalkylalkyl, amino, alkylamino, dialkylamino, —OCF₃,            acyloxy, —OR⁸, —C(O)R⁹, —C(O)OR⁸, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁸,            —NR¹⁰S(O)₂R⁹, —S(O)₀₋₂R⁹ groups, carbonyl when two hydrogens            attached to the same carbon atom of the cycloalkyl or            heterocycloalkyl group of R′ are substituted, and ═CR⁸R⁹            when two hydrogens attached to the same carbon atom of the            cycloalkyl or heterocycloalkyl groups of R¹ are substituted,        -   wherein each of the aryl, heteroaryl, cycloalkyl and            heterocycloalkyl groups of the R³ and R⁴ moieties above is            independently unsubstituted or substituted with 1 to 5            independently selected R¹² moieties which can be the same or            different, each R¹² moiety being independently selected from            the group consisting of: halo, phenyl, nitro, cyano,            haloalkyl, haloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl,            amino, alkylamino, —OCF₃, acyloxy, —OR⁸, —C(O)R⁹, —C(O)OR⁸,            —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁸, —NR¹⁰S(O)₂R⁹, —S(O)₀₋₂R⁹ groups,            carbonyl when two hydrogens attached to the same carbon atom            of the cycloalkyl or heterocycloalkyl group of R³ or R⁴ are            substituted, and ═CR⁸R⁹ when two hydrogens attached to the            same carbon atom of the cycloalkyl or heterocycloalkyl group            of R³ or R⁴ are substituted; or    -   iii) R^(a) and R^(b), together with the carbon to which they are        both attached, form a 4- to 7-membered cycloalkyl or        heterocycloalkyl ring, and R^(c) and R^(d) are each        independently H or an alkyl group; or    -   iv) R^(a) and R^(c), together with the respective carbons to        which they are attached, form a 4- to 7-membered cycloalkyl or        heterocycloalkyl ring, and R^(b) and R^(d) are each        independently H or an alkyl group, preferably R^(a) and R^(c)        together have the cis configuration, e.g., where the carbons        carrying R^(a) and R^(c) have the R and S configurations,        respectively;    -   v) R² is H, halo, alkyl, haloalkyl, alkoxy, alkylthio, amino,        aminosulfonyl, monoalkylamino, dialkylamino, hydroxyalkylamino,        aminoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl or        alkylaminocarbonyl group,        -   wherein each alkyl group of R² is independently            unsubstituted or substituted with 1 to 5 independently            selected R¹³ moieties which can be the same or different,            each R¹³ moiety being independently selected from the group            consisting of halo, hydroxy, alkoxy, alkyl, aryl (e.g.,            phenyl, naphthyl) heteroaryl (e.g., 1H-imidazol-2-yl),            cycloalkyl, heterocycloalkyl (e.g., pyrrolidin-1-yl), amino,            monoalkylamino or dialkylamino group,        -   wherein each aryl group of R¹³ is independently            unsubstituted or substituted with 1 to 5 independently            selected R⁴ moieties which can be the same or different;    -   vi) Y is H or an alkyl group substituted with (i) an aryl,        heteroaryl, cycloalkyl, hydroxy, alkoxy, amino, monoalkylamino        or dialkylamino group, or (ii) an aryl group substituted with        from one to three moieties each independently selected from the        group consisting of: halo, alkyl, phenyl, hydroxy, alkoxy,        phenoxy, amino, monoalkylamino and dialkylamino group;    -   vii) each R⁸ is independently H, alkyl or aryl;    -   viii) each R⁹ is independently H, alkyl, aryl or —NR¹⁰R¹¹;    -   ix) each R¹⁰ is independently H, alkyl, aryl, heteroaryl,        arylalkyl or heteroarylalkyl, wherein each alkyl, aryl,        heteroaryl, arylalkyl or heteroarylalkyl of R¹⁰ is unsubstituted        or independently substituted with 1 to 5 R¹⁴ moieties which can        be the same or different, each R¹⁴ moiety being independently        selected from the group consisting of: halo, alkyl, aryl,        cycloalkyl, —CF₃, —OCF₃, —CN, —OR⁸, —CH₂OR⁸, —C(O)OR⁸ and        —C(O)NR⁸R⁸; and    -   x) each R¹¹ is independently H, alkyl, aryl, heteroaryl,        arylalkyl or heteroarylalkyl, wherein each alkyl, aryl,        heteroaryl, arylalkyl or heteroarylalkyl of R¹¹ is unsubstituted        or independently substituted with 1 to 5 R¹⁴ moieties which can        be the same or different.

The invention further provides the use of PDE 1 Inhibitors of FormulaVIIa or VIIb, in free or salt form, as follows:

-   -   4.1: Formula VIIa or VIIb, wherein q=0, 1 or 2;    -   4.2: Formula VIIa or VIIb, wherein q=0;    -   4.3: Formula VIIa or VIIb or 4.1 or 4.2, wherein R₁ is alkyl;    -   4.4: Formula VIIa or VIIb or 4.1-4.3, wherein R¹ is methyl;    -   4.5: Formula VIIa or VIIb or 4.1-4.4, wherein R^(a) and R^(c),        together with the respective carbons to which they are attached,        form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and        R^(b) and R^(d) are each independently H or an alkyl group;    -   4.6: Formula VIIa or VIIb or 4.1-4.4, wherein R^(a) and R^(c),        together with the respective carbons to which they are attached,        form a 5-membered heterocycloalkyl ring, and R^(b) and R^(d) are        each independently H,    -   4.7: Formula 4.6 wherein R^(a) and R^(c) together have a cis        configuration;    -   4.8: Formula VIIa or VIIb or 4.1-4.4, wherein R^(a) and R^(b),        together with the respective carbons to which they are attached,        form a 5-membered heterocycloalkyl ring, and R^(c) and R^(d) are        each independently H,    -   4.9: Formula VIIa or VIIb or 4.1-4.7, wherein R² is alkyl or        haloalkyl;    -   4.10: Formula VIIa or VIIb or 4.1-4.7, wherein R² is        biphenyl-4-ylmethyl;    -   4.11: Formula VIIa or VIIb or 4.1-4.7, wherein R² is benzyl;    -   4.12: Formula VIIa or VIIb or 4.1-4.7, wherein R² is        cyclopentylmethyl;    -   4.13: Formula VIIa or VIIb or 4.1-4.7, wherein R² is        cyclopropylmethyl; and/or    -   4.14: Formula VIIa or VIIb or 4.1-4.12, wherein Y is benzyl;    -   4.15: Of any of the preceding formulae wherein the compound is        selected from the following:

-   -   4.16: Of any of the preceding formulae wherein the compound is

-   -   in free or salt form;    -   4.17: A compound which is a substituted        imidazo[2,1-b]purin-4-one, in free or pharmaceutically        acceptable salt form, e.g. a compound of Formula VIIa or        according to any of formulae 4.1-4.16, wherein the compound        inhibits phosphodiesterase-mediated (e.g., PDE1-mediated,        especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an        IC₅₀ of less than 1 μM, preferably less than 25 nM in an        immobilized-metal affinity particle reagent PDE assay, for        example, as described in Example 1 below.

Preferably, compounds of Formula VIIa or VIIb are selected from a groupconsisting of(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2,3-bis(phenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one,(6aR,9aS)-2-(biphenyl-4-ylmethyl)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl)cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one,5′-methyl-2′,3′-bis(phenylmethyl)spiro[cyclopentane-1,7′(8′H)-[3H]imidazo[2,1-b]purin]-4′(5′H)-oneand5′-methyl-2′-(biphenyl-4-ylmethyl)-3′-(phenylmethyl)spiro-[cyclopentane-1,7′(8′H)-[3H]imidazo[2,1-b]purin]-4′(5′H)-one,in free or pharmaceutically acceptable salt form.

In an especially preferred embodiment, compound of Formula VIIa is(6aR,9aS)-2-(biphenyl-4-ylmethyl)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one,in free or salt form.

The numbering of substituted imidazo[2,1-b]purin-4-one of Formula VIIaor VIIb as described herein is shown below as an example, wherein q=0:

wherein q=1:

In another embodiment, the PDE 1 Inhibitors for use in the methods oftreatment described herein are Compounds of Formula VIIIa or VIIIb:

in free or salt form, wherein:

-   -   J is oxygen or sulfur,    -   R¹ is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;    -   R² is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl        substituted with aryl, heteroaryl, hydroxy, alkoxy, amino,        monoalkyl amino or dialkylamino, or —(CH₂)_(m) TCOR²⁰ wherein m        is an integer from 1 to 6, T is oxygen or —NH— and R²⁰ is        hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl        or heteroaryl;    -   R³ is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl,        cycloalkyl, aryl, aminosulfonyl, amino, monoalkylamino,        dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy,        alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl,        hydroxy, alkoxy, amino, monoalkylamino or dialkylamino;    -   R^(a), R^(b), R^(c) and R^(d) independently represent hydrogen,        alkyl, cycloalkyl or aryl; or (R^(a) and R^(b)) or (R^(c) and        R^(d)) or (R^(b) and R^(c)) can complete a saturated ring of 5-        to 7-carbon atoms, or (R^(a) and R^(b)) taken together and        (R^(b) and R^(c)) taken together, each complete a saturated ring        of 5- to 7-carbon atoms, wherein each ring optionally can        contain a sulfur or oxygen atom and whose carbon atoms may be        optionally substituted with one or more or the following:        alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or        alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or        such saturated ring can have two adjacent carbon atoms which are        shared with an adjoining aryl ring; and    -   n is zero or one.

The invention further provides the use of PDE 1 Inhibitors of FormulaVIIIa or VIIIb as follows:

-   -   5.1: Formula VIIIa or VIIIb, wherein J=O    -   5.2: Formula VIIIa or VIIIb or 5.1, wherein R¹ is alkyl.    -   5.3: Formula VIIIa or VIIIb, 5.1 or 5.2, wherein R² is hydrogen,        benzyl, 4-chlorobenzyl, cyclohexylmethyl or        trimethylacetoxymethyl.    -   5.4: Formula VIIIa or VIIIb, 5.1, 5.2 or 5.3, wherein R³ is        hydrogen, or alkyl such as methyl or ethyl.    -   5.5: Formula VIIIa or VIIIb, 5.1, 5.2, 5.3 or 5.4, wherein n is        zero; and    -   5.6: Formula VIIIa or VIIIb, 5.1, 5.2, 5.3, 5.4 or 5.5, wherein        R^(a) and R^(b) form a saturated 5 membered ring, or (R^(b) and        R^(c)) form a saturated 5, 6 or 7 membered ring, or (R^(a) and        R^(b)) and (R^(b) and R^(c)) each complete a saturated ring and        each ring contains 5 or 6 carbon atoms.    -   5.7 Formula VIIIa or VIIIb, in free or salt form, selected from        the following:

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(phenylmethyl)cyclopenta[4,5]imidazo-[2,1-b]purin-4-one;

-   7,8-Dihydro-5-methyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-3-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4(5H)-one;

-   5,7,8,9-Tetrahydro-5-methyl-3-(phenylmethyl)pyrimido[2,1-b]purin-4(3H)-one;

-   7,8-Dihydro-8-phenyl-5-methyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   5′,7′-Dihydro-5′-methyl-3′-(phenylmethyl)spiro[cyclohexane-1,8′-(8H)imidazo-[2,1-b]purin]-4′(3′H)-one;

-   cis-5,6a,11,11a-Tetrahydro-5-methyl-3-(phenylmethyl)indeno[1′,2′:4,5]imidazo-[2,1-b]purin-4(3H)-one;

-   5′,7′-Dihydro-2′,5′dimethyl-3′-(phenylmethyl)spiro{cyclohexane-1,7′(8′H)-imidazo[2,1-b]purin}-4′-(3′H)-one;

-   7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3H-imidazo[2,1-b]purin-4(5H)-one;

-   cis-5,6a,7,11b-Tetrahydro-5-methyl-3-(phenylmethyl)indeno[2′,1′,4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent[4,5]-imidazo[2,1-b]purin-4-(3H)-one;

-   5′-Methyl-3′-(phenylmethyl)-spiro[cyclopentane-1,7′-(8′H)-(3′H)imidazo[2,1-b]purin]-4-(5′H)-one;

-   7,8-Dihydro-2,5,7,7-tetramethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5′H)-one;

-   7,8-Dihydro-7(R)-phenyl-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-3,7(R)-bis(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   (±)-7,8-Dihydro-2,5-dimethyl-7-ethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   6a(S)-7,8,9,10,10a(R)-Hexhydro-2,5-dimethyl-3-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4(5H)-one;

-   6a(R)-7,8,9,10,10a(S)-hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H-benzimidazo-[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(R)-isopropyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5,7(R)-trimethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   cis-7,7a,8,9,10,10a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H-cyclopenta-[5,6]pyrimido[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(S)-(1-methylpropyl)-3-(phenylmethyl)-3H-imidazo-[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(R)-(2-methylpropyl)-3-(phenylmethyl)-3H-imidazo-[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(R,S)-(methoxycarbonyl)-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(R,S)-(1-propyl)-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(S)-(1-methylethyl)-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3H-imidazo[2,1-b]purin-4(5H)-one;

-   5,7,8,9-Tetrahydro-2,5,7,9(R,S)-pentamethyl-3-(phenylmethyl)-pyrimido[2,1-b]purin-4(3H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(S),7,8,9,9a(R)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-6a,7,8,9,10,10a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4(5H)-one;

-   5′,7′-Dihydro-2′,5′-dimethyl-3′-(phenylmethyl)spiro[cyclohexane-1,8-(8H)-imidazo[2,1-b]purin]-4-(3′H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclohept-[6,7]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4-(5H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-phenyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-2-phenyl-3-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4(5H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methylcyclopenta[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethylcyclopenta[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a(R),    7,8,9,9a(S)-Hexahydro-2,5-di-methylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   2′,5′-dimethyl-spiro{cyclopentane-1,7′-(8′H)-(3′H)-imidazo[2,1-b]purin}-4′(5′H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(R)-(1-methylethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5,7,7-tetramethyl-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7,8-Dihydro-2,5-dimethyl-7(S)-(1-methylethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   6a(R),7,8,9,10,10a(S)-Hexahydro-2,5-dimethyl-3H-benzimidazo[2,1-b]purin-4(5H)-one;

-   5′,7′-Dihydro-2′,5′-dimethylspiro{cyclohexane-1,7-(8′H)-imidazo[2,1-b]purin}-4′(3′H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(phenylmethyl)cyclopenta[4,5]-imidazo[2,1-b]purin-4(3H)-thione;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-thione;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(4-chlorophenylmethyl)cyclopenta[4,5]-imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(cyclohexylmethyl)cyclopent[4,5]-imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(2-naphthylmethyl)cyclopent[4,5]-imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-bromophenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(R)-7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-methoxyphenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2,3,5-trimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2-(hydroxymethyl)-5-methyl-3-(phenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2-methylthio-5-methyl-3-(Phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-3,4,5,6a,7,8,9,9a-Octahydro-5-methyl-4-oxo-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-2-carboxylic    acid;

-   cis-3,4,5,6a,7,8,9,9a-Octahydro-5-methyl-4-oxo-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-2-carboxylic    acid, methyl ester;

-   cis-5,6a,7,8,9,9a-Hexahydro-2-bromo-5-methyl-3-(phenylmethyl)cyclopent[4,5]imidazo[2,1-b]purin-4(3H)one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2-(methylaminosulfonyl)-5-methyl-3-(phenylmethyl)cyclopent[4,5]imidazo[2,1-b]purin-4(3H)one;

-   cis-1-Cyclopentyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]imidazo[2,1-b]purin-4-(1H)one;

-   cis-5,6a,7,8,9,9a-Hexahydro-3,5-bis-(phenylmethyl)cyclopent(4,5)imidazo[2,1-b]purin-4(3H)one;

-   cis-6a,7,8,9,10,10a-Hexahydro-3,5-bis-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4(5H)one;

-   cis-3-Cyclopentyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)one;

-   5′-Methyl-3′-(phenylmethyl)spiro[cyclopentane-1,7-(8′H)-(3′H)imidazo[2,1-b]purin]-4-(5H)one;

-   2′,5′-Dimethyl-3′-(phenylmethyl)-spiro[cyclopentane-1,7-(8′H)-(3H)imidazo[2,1-b]purin]-4-(5′H)one;

-   cis-5,6a,(R)7,8,9,9a(S)-Hexahydro-5-methyl-3-(phenylmethyl)cyclopent[4,5]-imidazo[2,1-b]purin-4(3H)one;

-   cis-3-Cyclopentyl-5,6a,7,8,9,9a-Hexahydro-2,5-dimethylcyclopent[4,5]imidazo-[2,1-b]purin-4(3H)one;

-   5′-Methyl-2′-trifluoromethyl-3′-(phenylmethyl)spiro{cyclo-pentane-1,7′(8′H)-(3′H)imidazo[2,1-b]purin}-4-(5′H)-one;

-   7,8-Dihydro-5,7,7-trimethyl-2-trifluoromethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(5H)-one;

-   (+/−)-cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-trifluoromethyl-3-(phenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   (+/−)-6a,7,8,9,9a,10,11,11a-Octahydro-2,5-dimethyl-3-(phenylmethyl)-3H-pentaleno[6a′,1′:4,5]imidazo[2,1-b]purin-4(5H)-one;

-   (+)-6a,7,8,9,9a,10,11,11a-Octahydro-2,5-dimethyl-3-phenylmethyl-3H-pentaleno[6a′,1′:4,5]imidazo[2,1-b]purin-4(5H)-one;

-   (−)-6a,7,8,9,9a,10,11,11a-Octahydro-2,5-dimethyl-3-phenylmethyl-3H-pentaleno[6a′,1′:4,5]Imidazo[2,1-b]purin-4(5H)-one;

-   (+/−)    6a,7,8,9,9a,10,11,11a-Octahydro-2,5-dimethyl-3H-pentaleno[6a′,1′:4,5]-imidazo[2,1-b]purin-4(5H)-one;

-   (+)-6a,7,8,9,9a,10,11,11a-Octahydro-2,5-dimethyl-3H-pentaleno[6a′,1′:4,5]-imidazo[2,1-b]purin-4(5H)-one;

-   (−)-6a,7,8,9,9a,10,11,11a-Octahydro-2,5-dimethyl-3H-pentaleno[6a′,1′:4,5]-imidazo[2,1-b]purin-4(5H)-one;

-   6a,7,8,9,10,10a,11,12,13,13a-Decahydro-2,5-dimethyl-(3-phenylmethyl)-napth[1,8a-d]imidazo[2,1-b]purin-4(5H)one;

-   7(R)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(3H)-one;

-   7(R)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3H-imidazo[2,1-b]purin-4(5H)-one;

-   7(S)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-4(3H)-one;

-   7(S)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3H-imidazo[2,1-b]purin-4(5H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-[3-(trimethylacetoxy)methyl]-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-pyridylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-[2-(4-morpholinyl)-ethyl]cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-[acetoxymethyl]cyclopent-[4,5]imidazo[2.1-b]purin-4(3H)-one;

-   5,6a,7,8,9,9a-Hexahydro-2,5,6a-trimethyl-3-(phenylmethyl)cyclopent-[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(R),7,8,9,9a(S)-Hexahydro-2,5,6a-trimethyl-3-(phenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   5,6a(S),7,8,9,9a(R)-Hexahydro-2,5,6a-trimethyl-3-(phenylmethyl)-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;

-   cis-6a,7,8,9,10,10a-Hexahydro-2,5,7-trimethyl-3-(phenylmethyl)-3H-benzimidazo[2,1-b]purin-4(5H)-one;

-   cis-5,6a,7,8,9,9a-Hexahydro-2,5,6a-trimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one;    or

-   cis-[6a,7,8,9,10,10a-Hexahydro-2,5,7-trimethyl-3H-benzimidazo[2,1-b]purin-4(5H)-one],    -   in free or salt form.    -   5.8: A compound which is a substituted        imidazo[2,1-b]purin-4-one, in free or pharmaceutically        acceptable salt form, e.g. a compound of Formula VIIIa, VIIIb or        according to any of formulae 5.1-5.7, wherein the compound        inhibits phosphodiesterase-mediated (e.g., PDE 1-mediated,        especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an        IC₅₀ of less than 10 μM, preferably less than 100 nM in an        immobilized-metal affinity particle reagent PDE assay, for        example, as described in Example 1 below.

In another embodiment, the PDE 1 Inhibitors for use in the methods oftreatment described herein are Compounds of Formula IXa or IXb

or a pharmaceutically acceptable salt thereof, wherein,q=0 or 1;R¹ is H, cycloalkyl, alkyl, R²³-alkyl- or R²⁶;R^(a), R^(b) and R^(c) are, independently of one another, each H, alkyl,cycloalkyl, aryl, R²²-aryl- or R²⁴-alkyl-; orR^(a) and R^(b), together with the carbon to which they are bothattached, form a 4- to 7-membered ring, and R^(c) is H or alkyl; orR^(a) and R^(c), together with the respective carbons to which they areattached, form a 4- to 7-membered ring, and R^(b) is H or alkyl;

-   -   (i) X is a bond;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is monohaloalkyl, polyhaloalkyl, provided that it is not            trifluoromethyl, azido, cyano, oximino, cycloalkenyl,            heteroaryl, R²²-heteroaryl- or R²⁷-alkyl-;    -   (ii) X is a bond;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is H, halo, —CONHR⁶, —CONR⁶R⁷, —CO₂R⁶, monohaloalkyl,            polyhaloalkyl, azido, cyano, —C═N—OR⁶, cycloalkyl,            cycloalkylalkyl, R²⁶, aminosulfonyl, alkyl or R²³-alkyl-    -   (iii) X is —O— or —S—;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is R²⁶, cycloalkyl cycloalkylalkyl, heterocycloalkyl,            cycloalkenyl or R²⁶-alkyl-;    -   (iv) X is —O— or —S—;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, cycloalkenyl or R²⁸-alkyl-;    -   (v) X is —SO— or —SO₂—;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, cycloalkenyl or R²⁸-alkyl-;    -   (vi) X is —NR⁸—;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is (R²⁹)_(p)-alkyl-, cycloalkyl, (R³⁰)_(p)-cycloalkyl-,            cycloalkenyl, (R³⁰)_(p)-cycloalkenyl-, heterocycloalkyl or            (R³⁰)_(p)-heterocycloalkyl-:    -   (vii) X is —NR⁸—;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, cycloalkenyl or R³¹-alkyl-; or    -   (viii) X is —C≡C—;        -   Y is aryl-alkyl or R²²-aryl-alkyl-; and        -   R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl or R²³-alkyl-;            where,    -   R⁶ is H or R⁷;    -   R⁷ is alkyl, cycloalkyl or cycloalkylalkyl;    -   R⁸ is heterocycloalkyl or R⁶;    -   R²¹ is 1-6 substituents each independently selected from the        group consisting of halo, hydroxy, alkoxy, phenoxy, phenyl,        nitro, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl,        thiol, alkylthio, cycloalkyl, cycloalkylalkyl, amino,        alkylamino, acylamino, carboxyl, —C(O)OR³⁴, carboxamido, —OCF₃        and acyloxy;    -   R²² is 1-6 substituents each independently selected from the        group consisting of alkyl and R²¹;    -   R²³ is cycloalkoxy aryloxy, alkylthio, arylthio, cycloalkyl or        R²⁸;    -   R²⁴ is cycloalkyl or R²⁶;    -   R²⁵ is hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or        R²⁶;    -   R²⁶ is aryl, R²²-aryl-, heteroaryl or R²²-heteroaryl-;    -   R²⁷ is cycloalkoxy, aryloxy, alkylthio, arylthio, heteroaryl,        R²²-heteroaryl-, cycloalkyl, heterocycloalkyl, cycloalkenyl,        cycloalkylamino or heterocycloalkylamino;    -   R²⁸ is cycloalkylamino, heterocycloalkylamino or R²⁵;    -   R²⁹ is alkoxy, cycloalkylamino, heterocycloalkylamino or R²⁶;    -   R³⁰ is halo, hydroxy, alkoxy, amino, aminosulfonyl, cyano,        monohaloalkyl, polyhaloalkyl, thiol, alkylthio, alkyl,        cycloalkyl, cycloalkylalkyl or acyloxy;    -   R³¹ is cycloalkyl or R²⁸;    -   R³⁴ is alkyl, aryl, aralkyl and heteroaryl; and    -   p is 1 to 4.

The invention further provides the use of PDE 1 Inhibitors of FormulaIXa or IXb as follows:

-   -   6.1 Formula IXa or IXb selected from a group consisting of:

-   -   6.2 Formula IXa or IXb, in free or salt form, selected from a        group consisting of:

in free or salt form.

In another embodiment, the invention provides the use of PDE 1Inhibitors of Formula X:

in free or a pharmaceutically acceptable salt thereof, wherein:R₁, R₂ and R₃ are independently selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, halogeno, hydroxy, (di-loweralkyl)amino, 4-morpholinyl, 1-pyrrolidinyl, 1-pyrrolyl, —CF₃, —OCF₃,phenyl and methoxyphenyl; or R₁ and R₂ together are methylenedioxy; orR₁ and R₂ together with the carbon atoms to which they are attached forma benzene ring; andR^(a) is hydrogen and R^(b) and R^(c), together with the carbon atoms towhich they are attached, form a saturated ring of 5 carbons; or R^(a) islower alkyl, R^(b) is hydrogen or lower alkyl, and R^(c) is hydrogen; orR^(a), R^(b) and the carbon atom to which they are attached form asaturated ring of 5-7 carbons, and R^(c) is hydrogen; or R^(a) ishydrogen, and R^(b), R^(c) and the carbon atoms to which they areattached form a tetrahydrofuran ring; or R^(a) and R^(b), together withthe carbon atom to which they are attached, and R^(b) and R^(c),together with the carbon atoms to which they are attached, each form asaturated ring of 5-7 carbons.

In a further embodiment, the invention provides the use of PDE 1Inhibitors of Formula X as follows:

-   -   7.1 Formula X, wherein R₁, R₂ and R₃ are independently selected        from the group consisting of hydrogen, lower alkyl, lower        alkoxy, halogeno, hydroxy, (di-lower alkyl)amino, 4-morpholinyl,        1-pyrrolidinyl, 1-pyrrolyl, —CF₃, —OCF₃, phenyl and        methoxyphenyl; or R₁ and R₂ together are methylenedioxy; or R₁        and R₂ together with the carbon atoms to which they are attached        form a benzene ring;    -   7.2 Formula X or 7.1, wherein R₁ is H, methoxy or        trifluoromethyl;    -   7.3 Formula X or 7.1 or 7.2, wherein R₁ is H,    -   7.4 Formula X or any of 7.1-7.3, wherein R₂ is selected from a        group consisting of H, halo (e.g., F, Cl), methoxy, methyl,        trifluoromethyl, dimethylamino, phenyl, methoxyphenyl-, —OCF₃,        3,4-OCH₂O—, pyrrolidin-1-yl, pyrol-1-yl and morpholin-4-yl;    -   7.5 Formula X or any of 7.1-7.4, wherein R₁ and R₂ together with        the carbon atoms to which they are attached form a benzene ring;    -   7.6 Formula X or any of 7.1-7.5, wherein R₃ is H or methoxy;    -   7.7 Formula X or any of 7.1-7.6, wherein R₃ is H;    -   7.8 Formula X or any of 7.1-7.7, wherein R^(a) is hydrogen and        R^(b) and R^(c), together with the carbon atoms to which they        are attached, form a saturated ring of 5 carbons; or R^(a) is        lower alkyl, R^(b) is hydrogen or lower alkyl, and R^(c) is        hydrogen; or R^(a), R^(b) and the carbon atom to which they are        attached form a saturated ring of 5-7 carbons, and R^(c) is        hydrogen; or R^(a) is hydrogen, and R^(b), R^(c) and the carbon        atoms to which they are attached form a tetrahydrofuran ring; or        R^(a) and R^(b), together with the carbon atom to which they are        attached, and R^(b) and R^(c), together with the carbon atoms to        which they are attached, each form a saturated ring of 5-7        carbons;    -   7.9 Formula X or any of 7.1-7.8, wherein R^(a) is hydrogen and        R^(b) and R^(c) together with the carbon atoms to which they are        attached, form a saturated ring of 5 carbons, and wherein R₁, R₂        and R₃ are as defined in the following table

R₁ R₂ R₃ H H H —OCH₃ H H H F H H —OCH₃ H H OH H H —CH₃ H H (CH₃)₂N— H—OCH₃ —OCH₃ —OCH₃ —OCH₃ —OCH₃ H —CF₃ H H H C₆H₅— H H —OCF₃ H H

H H

H 3,4-OCH₂O— H H

H H

H R₁ and R₂, together with the H carbon atoms to which they are attachedform a benzene ring H Cl H.

-   -   7.10 Formula X or any of 7.1-7.9, selected from a group        consisting of

-   -   7.11 Formula X or any of 7.1-7.9, selected from a group        consisting of:

-   2′-benzyl-5′-methyl-spiro[cyclopentane-1′,7′(8′H)-[3′H]-imidazo[2,1-b]purin]-4′-(5′H)-one;

-   2′-benzyl-5,7,7-trimethyl-3H-imidazo[2,1-b]purin-4-(5H)-one;

-   (+)-2-benzyl-7,8-dihydro-5-methyl-7-(1-methylethyl)-1H-imidazo[2,1-b]-purin-4(5H)-one;

-   (+,−)-6a,7,8,9,9a,10,11,11a-octahydro-5-methyl-2-(3,4-methylene-dioxyphenylmethyl)-3H-pentalen[6a,1:4,5]imidazo[2,1-b]purin-4(5H)-one;    and

-   (+)-cis-6a,7,9,9a-tetrahydro-5-methyl-2-[4-(trifluoromethyl)-phenylmethyl]-3H-furo[3′,4′:4,5]imidazo[2,1-b]purin-4(5H)-one,    -   in free or salt form.    -   7.12 Formulae X or 7.1-7.11, wherein the compounds inhibit        phosphodiesterase-mediated (e.g., PDE1-mediated, especially        PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC₅₀ of less        than 1 μM, preferably less than 25 nM in an immobilized-metal        affinity particle reagent PDE assay, for example, as described        in Example 1;

In another embodiment, the invention provides the use of PDE 1Inhibitors selected from the following:

in free or salt form (Formula XI).

If not otherwise specified or clear from context, the following terms asused herein have the following meanings:

-   -   a. “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, preferably saturated, preferably one to        seven carbon atoms in length, which may be linear or branched,        and may be optionally substituted, e.g., mono-, di-, or        tri-substituted, e.g., with halogen (e.g., chloro or fluoro),        hydroxy, or carboxy.    -   b. “Cycloalkyl” as used herein is a saturated or unsaturated        nonaromatic hydrocarbon moiety, preferably saturated, preferably        comprising three to nine carbon atoms, at least some of which        form a nonaromatic mono- or bicyclic, or bridged cyclic        structure, and which may be optionally substituted, e.g., with        halogen (e.g., chloro or fluoro), hydroxy, or carboxy.    -   c. “Heterocycloalkyl” as used herein is a saturated or        unsaturated nonaromatic hydrocarbon moiety, preferably        saturated, preferably comprising three to nine carbon atoms, at        least one atom selected from a group consisting of N, O or S, at        least some of which form a nonaromatic mono- or bicyclic, or        bridged cyclic structure, and which may be optionally        substituted, e.g., with halogen (e.g., chloro or fluoro),        hydroxy, or carboxy. Examples of heterocycloalkyl include        pyrrolidinyl (e.g., pyrrolidin-1-yl), morpholinyl (e.g.,        morpholin-4-yl),    -   d. “Aryl” as used herein is a mono or bicyclic aromatic        hydrocarbon (e.g., phenyl, naphthyl), preferably phenyl,        optionally substituted, e.g., with alkyl (e.g., methyl), halogen        (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl),        hydroxy, carboxy, or an additional aryl or heteroaryl (e.g.,        biphenyl or pyridylphenyl).    -   e. “Heteroaryl” as used herein is an aromatic moiety wherein one        or more of the atoms making up the aromatic ring is sulfur or        nitrogen rather than carbon, e.g., pyridyl, thiadiazolyl,        pyrrolyl (e.g., pyrrol-2-yl) or imidazolyl (e.g.,        1H-imidazol-2-yl), which may be optionally substituted, e.g.,        with alkyl, halogen, haloalkyl, hydroxy or carboxy.

PDE 1 Inhibitors may exist in free or salt form, e.g., as acid additionsalts. In this specification unless otherwise indicated language such asPDE 1 Inhibitors is to be understood as embracing the compounds in anyform, for example free or acid addition salt form, or where thecompounds contain acidic substituents, in base addition salt form. ThePDE 1 Inhibitors are intended for use as pharmaceuticals, thereforepharmaceutically acceptable salts are preferred. Salts which areunsuitable for pharmaceutical uses may be useful, for example, for theisolation or purification of free PDE 1 Inhibitors or theirpharmaceutically acceptable salts.

PDE 1 Inhibitors may in some cases also exist in prodrug form, forexample when the compounds contain physiologically hydrolysable andacceptable esters. As used herein, “physiologically hydrolysable andacceptable ester” means esters of PDE 1 Inhibitors which arehydrolysable under physiological conditions to yield acids (in the caseof PDE 1 Inhibitors which have hydroxy substituents) or alcohols (in thecase of PDE 1 Inhibitors which have carboxy substituents) which arethemselves physiologically tolerable at doses to be administered. Aswill be appreciated the term thus embraces conventional pharmaceuticalprodrug forms.

Methods of making and formulating the PDE 1 Inhibitors, novelintermediates useful for making PDE 1 Inhibitors, and methods of usingthe PDE 1 Inhibitors for treatment of diseases are generally disclosedin EP 0201188 (or U.S. Pat. No. 4,666,908) and EP 0911333 (or U.S. Pat.No. 6,235,742); PCT/US2006/022066; PCT/US2006/033179; WO 03/042216 (U.S.Pat. No. 6,943,171); U.S. Pat. No. 6,969,719; U.S. Pat. No. 5,939,419;EP 0 538 332 (U.S. Pat. No. 5,393,755); U.S. Pat. No. 5,393,755; U.S.Pat. No. 6,969,719 B2, Xia et al., J. Med. Chem. (1997), 40, 4372-4377and Ahn et al., J. Med. Chem. (1997), 40, 2196-2210, the contents of allof which are incorporated herein by reference.

Methods of Treatment

The invention provides methods of treatment or prophylaxis of narcolepsycomprising administering an effective amount of a PDE 1 inhibitor, e.g.,a PDE 1 Inhibitor as hereinbefore described, for example a Compound ofany of Formulae I, Ia, II, III, IV, V, VI, VIIa, VIIb, VIIIa, VIIIb,IXa, IXb, X, XI or any of Formulae 1.2-1.17, 2.1-2.9, or 3.2-3.22,4.1-4.17, 5.1-5.8, 6.1-6.1 or 7.1-7.12 to a human or animal patient,preferably a human, in need thereof.

PDE 1 Inhibitors may be used in the foregoing methods of treatmentprophylaxis as a sole therapeutic agent, but may also be used incombination or for co-administration with other active agents. Thus, theinvention further comprises a method of treating narcolepsy comprisingadministering simultaneously, sequentially, or contemporaneouslyadministering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor, e.g., any of Formulae I, Ia, II, III, IV,        V, VI, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, X, XI or any of        Formulae 1.2-1.17, 2.1-2.9, 3.2-3.22, 4.1-4.17, 5.1-5.8, 6.1-6.2        or 7.1-7.12; and    -   (ii) a compound to promote wakefulness or regulate sleep, e.g.,        selected from (a) central nervous system stimulants-amphetamines        and amphetamine like compounds, e.g., methylphenidate,        dextroamphetamine, methamphetamine, and pemoline; (b)        modafinil, (c) antidepressants, e.g., tricyclics (including        imipramine, desipramine, clomipramine, and protriptyline) and        selective serotonin reuptake inhibitors (including fluoxetine        and sertraline); and/or (d) gamma hydroxybutyrate (GHB),        to a patient in need thereof.

The present invention also provides

(i) a PDE 1 Inhibitor for use in the treatment of any disease orcondition as hereinbefore set forth, or in a method of treatment ashereinbefore set forth;

(ii) the use of a PDE 1 Inhibitor in the manufacture of a medicament fortreating a disease or condition as hereinbefore set forth, ormanufacture of a medicament for use in a method of treatment ashereinbefore set forth; and

(iii) a pharmaceutical composition comprising a PDE 1 Inhibitor incombination or association with a pharmaceutically acceptable diluent orcarrier for use in the treatment of a disease or condition ashereinbefore set forth, or for use in a method of treatment ashereinbefore set forth.

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of any of thesymptoms of disease as well as treatment of the cause of the disease.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular PDE 1 Inhibitor used, the mode of administration, and thetherapy desired. PDE 1 Inhibitors may be administered by any suitableroute, including orally, parenterally, transdermally, or by inhalation,but are preferably administered orally. In general, satisfactoryresults, e.g. for the treatment of diseases as hereinbefore set forthare indicated to be obtained on oral administration at dosages of theorder from about 0.01 to 2.0 mg/kg. In larger mammals, for examplehumans, an indicated daily dosage for oral administration willaccordingly be in the range of from about 0.75 to 150 mg, convenientlyadministered once, or in divided doses 2 to 4 times, daily or insustained release form. Unit dosage forms for oral administration thusfor example may comprise from about 0.2 to 75 or 150 mg, e.g. from about0.2 or 2.0 to 50, 75 or 100 mg of a PDE 1 Inhibitor, together with apharmaceutically acceptable diluent or carrier therefor.

Pharmaceutical compositions comprising PDE 1 Inhibitors may be preparedusing conventional diluents or excipients and techniques known in thegalenic art. Thus oral dosage forms may include tablets, capsules,solutions, suspensions and the like.

EXAMPLES 1. Measurement of PDE1B Inhibition In Vitro Using IMAPPhosphodiesterase Assay Kit

Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin dependentphosphodiesterase enzyme that converts cyclic guanosine monophosphate(cGMP) to 5′-guanosine monophosphate (5′-GMP). PDE1B can also convert amodified cGMP substrate, such as the fluorescent moleculecGMP-fluorescein, to the corresponding GMP-fluorescein. The generationof GMP-fluorescein from cGMP-fluorescein can be quantitated, using, forexample, the IMAP (Molecular Devices, Sunnyvale, Calif.)immobilized-metal affinity particle reagent.

Briefly, the IMAP reagent binds with high affinity to the free5′-phosphate that is found in GMP-fluorescein and not incGMP-fluorescein. The resulting GMP-fluorescein-IMAP complex is largerelative to cGMP-fluorescein. Small fluorophores that are bound up in alarge, slowly tumbling, complex can be distinguished from unboundfluorophores, because the photons emitted as they fluoresce retain thesame polarity as the photons used to excite the fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot be boundto IMAP, and therefore retains little fluorescence polarization, isconverted to GMP-fluorescein, which, when bound to IMAP, yields a largeincrease in fluorescence polarization (Δmp). Inhibition ofphosphodiesterase, therefore, is detected as a decrease in Δmp.

Enzyme Assay

Materials: All chemicals are available from Sigma-Aldrich (St. Louis,Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMPand IMAP beads), which are available from Molecular Devices (Sunnyvale,Calif.).

Assay: 3′,5′-cyclic-nucleotide-specific bovine brain phosphodiesterase(Sigma, St. Louis, Mo.) is reconstituted with 50% glycerol to 2.5 U/ml.One unit of enzyme will hydrolyze 1.0 μmole of 3′,5′-cAMP to 5′-AMP permin at pH 7.5 at 30° C. One part enzyme is added to 1999 parts reactionbuffer (30 μM CaCl₂, 10 U/ml of calmodulin (Sigma P2277), 10 mM Tris-HClpH 7.2, 10 mM MgCl₂, 0.1% BSA, 0.05% NaN₃) to yield a finalconcentration of 1.25 mU/ml. 99 μl of diluted enzyme solution is addedinto each well in a flat bottom 96-well polystyrene plate to which 1 μlof test compound dissolved in 100% DMSO is added. The compounds aremixed and pre-incubated with the enzyme for 10 min at room temperature.

The FL-GMP conversion reaction is initiated by combining 4 parts enzymeand inhibitor mix with 1 part substrate solution (0.225 μM) in a384-well microtiter plate. The reaction is incubated in dark at roomtemperature for 15 min. The reaction is halted by addition of 60 μl ofbinding reagent (1:400 dilution of IMAP beads in binding buffersupplemented with 1:1800 dilution of antifoam) to each well of the384-well plate. The plate is incubated at room temperature for 1 hour toallow IMAP binding to proceed to completion, and then placed in anEnvision multimode microplate reader (PerkinElmer, Shelton, Conn.) tomeasure the fluorescence polarization (Δmp).

A decrease in GMP concentration, measured as decreased Δmp, isindicative of inhibition of PDE activity. IC₅₀ values are determined bymeasuring enzyme activity in the presence of 8 to 16 concentrations ofcompound ranging from 0.0037 nM to 80,000 nM and then plotting drugconcentration versus ΔmP, which allows IC₅₀ values to be estimated usingnonlinear regression software (XLFit; IDBS, Cambridge, Mass.).

What is claimed is:
 1. A method of treatment for narcolepsy comprisingadministering an effective amount of a PDE 1 inhibitor to a patient inneed thereof wherein the PDE 1 inhibitor is a compound of the formula(I):

wherein (i) R₁ is H or C₁₋₄ alkyl; (ii) R₄ is H or C₁₋₄ alkyl and R₂ andR₃ are, independently, H or C₁₋₄ alkyl, aryl, heteroaryl,heteroarylalkoxy, arylalkoxy, heteroarylalkyl, or arylalkyl; or R₂ is Hand R₃ and R₄ together form a di-, tri-, or tetra-methylene bridge;(iii) R₅ is a substituted heteroarylalkyl, or R₅ is attached to one ofthe nitrogen atoms on the pyrazolo portion of Formula I and is a moietyof Formula Q

wherein X, Y and Z are, independently, N or C; R₈, R₉, R₁₁ and R₁₂ areindependently H or halogen; and R₁₀ is halogen, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or thiadiazolyl, diazolyl, triazolyl,tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, oralkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R₈, R₉, orR₁₀, respectively, is not present; (iv) R₆ is phenylamino orbenzylamino; and (v) n=0; wherein: said aryl is optionally substitutedwith alkyl, halogen, haloalkyl, hydroxy, carboxy or an additional arylor heteroaryl; and said heteroaryl is optionally substituted with alkyl,halogen, haloalkyl, hydroxy or carboxy, in free, pharmaceuticallyacceptable salt or prodrug form.
 2. The method according to claim 1wherein the PDE 1 inhibitor is a compound of Formula III:

wherein R₂ is H and R₃ and R₄ together form a tri- or tetra-methylenebridge; or at least one of R₂ and R₃ is methyl, isopropyl or arylalkoxyand R₄ is H; or R₂ and R₃ are H and R₄ is a C₁₋₄ alkyl; R₆ isphenylamino or benzylamino; R₁₀ is haloalkyl, phenyl, pyridyl, orthiadiazolyl; wherein: said phenyl is optionally substituted with alkyl,halogen, haloalkyl, hydroxy, carboxy or an additional aryl orheteroaryl; and said pyridyl and thiadiazolyl are optionally substitutedwith alkyl, halogen, haloalkyl, hydroxy or carboxy, in free orpharmaceutically acceptable salt form.
 3. The method according to claim1 wherein the PDE 1 inhibitor is a compound of Formula IV:

wherein R₂ is H and R₃ and R₄ together form a tri- or tetra-methylenebridge; or at least one of R₂ and R₃ is methyl, isopropyl or arylalkoxyand R₄ is H; or R₂ and R₃ are H and R₄ is a C₁₋₄ alkyl; R₆ isphenylamino or benzylamino; R₁₀ is phenyl, pyridyl, or thiadiazolyl;wherein: said phenyl is optionally substituted with alkyl, halogen,haloalkyl, hydroxy, carboxy or an additional aryl or heteroaryl; andsaid pyridyl and thiadiazolyl are optionally substituted with alkyl,halogen, haloalkyl, hydroxy or carboxy, in free or pharmaceuticallyacceptable salt form.
 4. The method according to claim 1 wherein the PDE1 inhibitor is a compound of formula Ia:

wherein (i) R₁ is H or C₁₋₄ alkyl; (ii) R₄ is H and R₂ and R₃ are,independently, H or C₁₋₄ alkyl, aryl, or arylalkyl; or R₂ is H and R₃and R₄ together form a di-, tri- or tetramethylene bridge; (iii) R₅ isattached to one of the nitrogens on the pyrazolo portion of formula Iand is a substituted benzyl of formula Qa

 wherein R₈, R₉, R₁₁ and R₁₂ are independently H or halogen; and R₁₀ ishalogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl,alkyl sulfonyl or heteroarylcarbonyl, and (iv) R₆ is phenylamino orbenzylamino wherein: said aryl is optionally substituted with alkyl,halogen, haloalkyl, hydroxy, carboxy or an additional aryl orheteroaryl; and said heteroaryl is optionally substituted with alkyl,halogen, haloalkyl, hydroxy or carboxy, in free, pharmaceuticallyacceptable salt or prodrug form.
 5. The method according to claim 1wherein the PDE 1 inhibitor is a compound of Formula V:

wherein R₂ is H and R₃ and R₄ together form a tri- or tetra-methylenebridge; or R₂ and R₃ are each methyl and R₄ is H; or R₂ and R₄ are H andR₃ is isopropyl; R₆ is phenylamino or benzylamino; R₁₀ is phenyl,pyridyl, or thiadiazolyl; wherein: said phenyl is optionally substitutedwith alkyl, halogen, haloalkyl, hydroxy, carboxy or an additional arylor heteroaryl; and said pyridyl and thiadiazolyl are optionallysubstituted with alkyl, halogen, haloalkyl, hydroxy or carboxy, in freeor pharmaceutically acceptable salt form.
 6. The method according toclaim 1, wherein the PDE 1 inhibitor inhibits phosphodiesterase-mediatedhydrolysis of cGMP or cAMP.
 7. The method according to claim 1, whereinthe PDE1 inhibitor is a PDE1B inhibitor.
 8. The method according claim 1further comprising administering a compound or compounds selected fromcentral nervous system stimulants, modafinil, antidepressants, and gammahydroxybutyrate.
 9. The method according to claim 1 wherein the PDE 1inhibitor is:

in free or pharmaceutically acceptable salt form.
 10. The methodaccording to claim 1, wherein R₁₀ is: aryl wherein said aryl issubstituted with alkyl, halogen, haloalkyl, hydroxy, carboxy or anadditional aryl or heteroaryl; or heteroaryl where said heteroaryl issubstituted with alkyl, halogen, haloalkyl, hydroxy or carboxy.
 11. Themethod according to claim 1, wherein R₆ is: phenylamino wherein saidphenyl is substituted with alkyl, halogen, haloalkyl, hydroxy, carboxyor an additional aryl or heteroaryl.
 12. The method according to claim5, wherein R₁₀ is pyridyl substituted with alkyl, halogen, haloalkyl,hydroxy or carboxy.